ACE2-cytomimetic particles restrict SARS-Cov-2 spike protein binding to cellular targets

•Epithelial cell-mimetic (rhACE2-cytomimetic) particles bind SARS-CoV-2 spike RBD.•rhACE2-Cytomimetic particles restrict SARS-CoV-2 spike binding to cell surface.•Particle functionalized rhACE2 is stoichiometrically superior to soluble rhACE2.•Inhaled rhACE2-Cytomimetic particles limit viral spike uptake in airway epithelium.•rhACE2-Cytomimetic particles can be an effective countermeasure for COVID-19. The development of countermeasures that aid in the prevention and propagation of SARS-CoV-2 infections is critical to manage the continuing crisis brought about by COVID-19. Here we present a proof-of-concept study on the use of cell-mimetic microparticles (Cytomimetics) for the interference and sequestration of SARS-CoV-2 virions away from the cellular surfaces required for replication, disease manifestation, and outbreak propagation. Recombinant human ACE2 (rhACE2) functionalized onto the surface of cytomimetic particles binds the receptor binding domain (RBD) of recombinant SARS-CoV-2 spike protein with high affinity and demonstrated a stoichiometric advantage over the use of soluble rhACE2. Inhalation of rhACE2-Cytomimetic particles by mice prior to their exposure to aerosolized spike protein demonstrated the applicability of these cytomimetic particles in preventing viral protein binding to respiratory epithelial cells. Our study demonstrates the potential of an easily deliverable and highly modular technology for the control of viral infections and to complement other prophylactic countermeasures